{8 (thiophosphonothio)acetamido{9 cephalosporin derivatives

ABSTRACT

WHEREIN R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group   R1 is hydrogen, lower alkyl, aralkyl, aryl or certain heterocyclic groups; R2 and R3 each is lower alkyl, aryl or aralkyl or R2 and R3 may together be two or three methylene groups joining in a 5- or 6-membered ring with the oxygen and phosphorus; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy,   THE RADICAL OF A NITROGEN BASE, A QUATERNARY AMMONIUM RADICAL, OR TOGETHER X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents. ((Thiophosphonothio)acetamido)cephalosporin derivatives of the general formula

' United States Patent [1 1 Treuner et al.

[ Oct. 21, 1975 i 1 [(THIOPHOSPHONOTHIO)ACETAMIDO]- CEPI-IALOSPORINDERIVATIVES [75] Inventors: Uwe D. Treuner, Regensburg;

Hermann Breuer, Burgweinting, both of Germany [57] ABSTRACT[(Thiophosphonothio)acetamido]cephalosporin derivatives of the generalformula [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: June 1, 1972 [21] Appl. No.: 258,687

[44] Published under the Trial Voluntary Protest Program on January 28,1975 as document no.

[52] U.S. Cl. 260/243 C; 424/246 [51] Int. Cl. Q. C07D 501/20 [58] Fieldof Search 260/243 C [56] References Cited UNITED STATES PATENTS3,578,661 5/197] Havranek 260/243 C Primary Examiner-Nicholas S. RizzoAttorney, Agent. or Firm-Lawrence S. Levinson; Merle J. Smith wherein Ris hydrogen. lower alkyl. aralkyl, tri(lower alkyl)silyl, tri(loweralkyl)stannyl, a salt forming ion or the group R, is hydrogen, loweralkyl, aralkyl. aryl or certain heterocyclic groups; R; and R each islower alkyl. aryl or aralkyl or R and R may together be two or threemethylene groups joining in a 5- or 6-membered ring with theoxygen andphosphorus; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy,aralkanoyloxy.

the radical of a nitrogen base, a quaternary ammonium radical, ortogether X and R represent a bond linking carbon and oxygen in a lactonering; are useful as antibacterial agents.

8 Claims, N0 Drawings [(THIOPHOSPHONOTHIO)ACETAMIDO]CEPH- ALOSPORINDERIVATIVES SUMMARY OF THE INVENTION This invention relates to new[(thiophosphonothio)acetamido]cephalosporin derivatives of the formulaygen), hydroxy, carboxy and the likeiln the case of the last two namedsubstituents there is preferably only" R represents hydrogen, loweralkyl, aralkyl, tri- (lower alkyl)silyl, tri(lower alkyl)stannyl, a saltforming ion or the group -CH -O-C-R 7 R represents hydrogen, loweralkyl, aryl," aralkyl or certain heterocyclic groups; R and R5,; whicha're preferably the same, each represents lower alkyl,'aryl or aralkylor R and R may join together to form a 2 or 3 and carbon polymethylenebridge completing a 5- or 6- membered ring with oxygen and phosphorus; Rrepresents lower alkyl, aryl or aralkyl. X is hydrogen, hy-

droxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy,

the radical of a nitrogen base, a quaternary ammonium radical, ortogether X and R represent a bond linking carbon and oxygen in a lactonering.

The preferred members within each group are as follows: R is hydrogen,lower alkyl, alkali metal, trimethy lsilyl or ll -CH2-O-C-R4,

especially hydrogen, methyl, pivaloyloxy, sodium or potassium; R isphenyl, thienyl, furyl or pyridyl, especially phenyl, R, and R; eachislower alkyl, especially methyl or ethyl; R is lower alkyl, preferablymethyl or t-butyl; and X is preferably hydrogen or acetoxy.

DETAILED o sckiarioN OF THE INVENTION The various groups represented bythe symbols have one, especially in the para position of the phenyl.Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mp-bromophenyl,3,4-dichlorophenyl. 3,5- dibromophenyl, o-, mand p-tolyl,p-methoxyphenyl, 3,4,5-trimethoxyphenyl. p-hydroxyphenyl, pcarboxyphenyland the like.

The aralkyl groups include a monocyclic carbocyclic aryl group attachedto a lower alkyl group, both as defined above. lllustrative are benzyl,o-, mor pchlorobenzyl, o-, mor p-bromobenzyl, o-. mor pmethylbenzyl,phenethyl, p-chlorophenethyl, 3,5- diethylbenzyl,3,4,5-trichlorobenzyland the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented byX include the acyl group of acid esters. The lower alkanoyl radicals arethe acyl radicals of lower fatty acids containing alkyl radicals of thetype described above. The lower alkanoyloxy groups include, for example,acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups arederived from monocyclic carbocyclic aryl groups of the kind described.Similarly the aralkanoyloxy groups consist of monocyclic carbocyclicaryl and alkanoyloxy radicals of the type described. The sulfurcontaining substituents represented by X bear the same type of groups. Xalso represents the radical of an amine, e.g., an alkylamine likemethylamine, ethylamine, dimethylamine, triethylamine, aralkylamine likedibenzylamine, pyridinium, l-quinolinium, l-picolinium, etc. X and R mayalso join together, as indicated above, to fonn a bond linkingcarbon'and oxygen in a lactone ring.

The heterocyclic groups represented by R are thienyl, furyl, pyridyl andisothiazolyl radicals as well as these heterocyclics with one or twosubstituents R, including halo, lower alkyl (particularly methyl andethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.

The salt forming ions represented by R may be metal ions, e.g.,aluminum, alkali metal ions such as sodium or potassium, alkaline earthmetal ions such as calcium or magnesium, or an amine salt ion, of whicha number are known for this purpose, for example, dibenzylamine, N,N-dibenzylethylenediamine, methylamine, triethylamine, procaine,N-ethylpiperidine, etc. The ester forming tri(lower alkyl)silyl andtri(lower alkyl)stannyl groups include, for example, trimethylsilyl,triethylsilyl, tri-n-butyl stannyl and the like.

R and R in addition to representing the individual substituentsindicated may together be two or three methylene groups, (e.g., derivedfrom ethylene glycol or propylene glycol) joining in a bridge which forma 5- or 6membered ring with the two oxygen atoms and 5 the phosphorus.

The new [(thiophosphonothio)acetamidolcephalosporin derivatives of thisinvention are produced by reacting a 7-aminocephalosporanic acidcompound of formula ll [which includes 7-aminocephalosporanic acid(7-ACA), 7-amino-3-desacetoxycephalosporanic acid (7-ADCA) and otherderivatives], or an activated derivative, of the formula (II) with adithiophosphoric acid ester of the formula (III) (III) R -CH-COOH l O-RS-P The dithiophosphoric acid esters of formula III are produced by thefollowing reaction n pa-coon S' O-R3 [The compounds of formula V areproduced by the method described in Houben-Weyl, Methoden derOrganischen Chemie, Vol. XII/2, pages 684-686 (1964)].

The halogen in the acid IV may be chlorine instead of 55 ambienttemperature or below.

As an alternative, a product of formula I may be probromine and thesodium as well as potassiumsalt of V may be used.

4 (VII) or other activating compound such as dicyclohexylcarbodiimide,along with a salt forming organic base, such as triethylamine, pyridineor the like, followed, after an interval, by the addition of the7-aminocephalosporanic acid compound. The product of the reaction isthen isolated by conventional procedures, e.g., by concentration orevaporation of the solvent.

When R is the acyloxymethyl group this groupmay be introduced into the7-aminocephalosporanic acid moiety prior to the reaction with thedithiophosphoric acid ester or the activated derivative by treatmentwith one to two moles of a halomethyl ester of the formula (VI) halCH-OCOR wherein hal is halogen, preferably chlorine or bromine, in an inertorganic solvent such as dimethylformamide, acetone, dioxane, benzene orthe like, at about duced by reacting a compound of the formula (VI!) ain the presence ofa tertiary alkylamine like triet hylamine, or with asalt of VIII, e.g., a metal salt such as an alkali metal salt, in asolvent such as dimethylformamide. Hal is halogen, preferably chlorineor bromine and R and R are the same as above. The metal salts areobtained by reacting a dithiophosphoric acid ester with the appropriatemetal in a lower alkanol or with the metal alkoxide, e.g., potassiumethoxide.

The compounds of this invention have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aurcus, Salmonella schottmuelleri, Pseudomonasaeruginosa, Proteus vulgaris,Escherichia coli and Streptococcuspyogenes. They may be used as antibacterial agents in a prophylacticmanner, e.g., in cleaning or disinfecting compositions, or otherwise tocombat infections due to organisms such as those named above, and ingeneral may be utilized in a manner similar to cephalothin and othercephalosporins. For example, a com pound of formula I or aphysiologically acceptable salt thereof may be used in various animalspecies in an amount of about I to 200 mg./kg., daily, orally orparenterally, in single or two to four divided doses to treat infectionsof bacterial origin, e.g., 5.0 mgjkg. in mice.

Oral forms give prompt high blood levels which are maintained forrelatively long periods.

Up to about 600 mg. of a compound of formula I or a physiologicallyacceptable salt thereof may be incorporated in an oral dosage form suchas tablets. capsules or elixirs or in an injectable form in a sterileaqueous 40 vehicle prepared according to conventional pharmaceuticalpractice.

They may also be used in cleaning or disinfecting compositions, e.g.,for cleaning barns or dairy equipment, at a concentration of about 0.01to 1% by weight of such compounds admixed with, suspended or dissolvedin conventional inert dry or aqueous carriers for application by washingor spraying. They are also useful as nutritional supplements in animalfeeds.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale. Additional variations may beproduced in the same manner by appropriate substitution in the startingmaterial.

EXAMPLE 1 7-[2-[ (Diethoxythiophosphono)thio]acetamido]cephalosporanicacid and potassium salt ELIE 2 g. (5 mM) of7-bromoacetamidocephalosporanic acid are dissolved in absolutedimethylformamide and a solution of 1.12 g. (SmM) of potassiumdithiophosphoric acid 0,0 diethyl ester is added. A precipitate ofpotassium bromide forms immediately. After stirring for 10 minutes, thereaction mixture is poured into 250 ml. of ice water and extracted threetimes with 100 ml. portions of ethyl acetate. The ethyl acetate extractsare combined. shaken with 2 X 50 ml. portions of water, then dried oversodium sulfate and concentrated. There are obtained 1.5 g. of lightyellow crystals of7.-[2-[(diethoxythiophosphono)thio]acetamido]cephalosporanic acid, m.p.(dec.); potassium salt m.p. l l5 (dec.).

EXAMPLE 2 7-[ 2-[ Diethoxythiophosphono)thio]-2phenylacetamidolcephalosporanic acid By substituting SmM of7-(2-bromo-2- phenylacetamido)-cephalosporanic acid for the 7-bromoacetamidocephalosporanic acid in the procedure of Example I, thereare obtained 2.] g. of yellow[(Dimethoxythiophosphono)thioIacetamidolcephalosporanic acid Bysubstituting SmM of potassium dithiophosphoric acid By substituting SmMof potassium dithiophosphoric acid dimethyl ester for the diethyl esterin the procedure of Example 1, 1.2 g. of 7-[2-[(dimethoxythiophosphono)thio]acetamido]-cephalosporanic acid areobtained as a viscous oil.

EXAMPLE 4 7- 2-[ (Diethoxythiophosphono thio acetamido]-3-desacetoxycephalosporanic acid By substituting SmM of7-bromo-3-desacetoxycephalosporanic acid for the7-bromoacetamidocephalosporanic acid inthe procedure of Example I, thereis obtained 7-[2- I(diethoxythiophosphono)thio]acetamido]-3-desacetoxycephalosporanic acid, m.p. 4814 50.

The following additional products having the formula in the right handside of the table are obtained by the procedure of Example 1 from thepotassium dithiophosphoric acid ester in the left hand part of the tableand the 7-bromoacetamidocephalosporanic acid having the indicated R andX substituents.

9 10 What is claimed is: 6; A compound as in claim 5 wherein eachalkyl 1. A compound of the formula group is ethyl.

S R -CH- CO NH CH -C|1H (Ill-I O-R 2 S-P N C-CH X l| O-R f 2 s ORwherein R is hydrogen, lower alkyl, phenyl-lower alkyl, 7. A compound asin claim 1 wherein R is hydrogen, tri(lower alkyl)silyl, tri( loweralkyl)stannyl, lower alkyl, alkali metal, trimethylsilyl or O O II II--CH -O-C-R CH O-CR 2 R and R each is lower alkyl; R, is lower alkyl;and aluminum, alkali metal, alkaline earth metal or tri(- X is hydrogenor acetoxy. lower alkyl)amine; R is phenyl, R and R each is lower 8. Acompound of the formula O-lower alkyl @TH- co-- NH CH CH (2H2 l s-P NC-CH x ll O-lower alkyl 0 4 2 S C-OR alkyl, phenyl-lower alkyl R, islower alkyl, or phenyl lower alkyl; and X is hydrogen, hydroxy or loweral- 0 kanoyloxy.

2. A compound as in claim 1 wherein R and R each is lower alkyl.

3. A compound as in claim 1 wherein R and X each is hydrogen, R and Reach is lower alkyl.

4. A compound as in claim I wherein R is hydrogen, R and R each is loweralkyl and X is acetoxy.

5. A compound as in claim 4 wherein each alkyl group is methyl.

40 wherein X is hydrogen, hydroxy or lower alkanoyloxy and R is hydrogenor alkali metal.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 v3914 221 DATED October 21, 1975 INVENTOR(S) Uwe D. Treuner, HermannBreuer It is certified'that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

In the Abstract under the definition of X after anoyloxy should beinserted SR 0R Column 6, line 33 delete "By substituting 5mM ofpotassium dithiophosphoric acid" Column 6, line 51 delete "l4" andinsert a hyphen Signed and Scaled this Nineteenth Day Of October 1976[SEAL] A nest:

RUTH C. MnSON C. MARSHALL DANN Atteslmg Ojjr'cer (mnmissiuner uflarenlsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R2 andR3 each is lower alkyl.
 3. A compound as in claim 1 wherein R and X eachis hydrogen, R2 and R3 each is lower alkyl.
 4. A compound as in claim 1wherein R is hydrogen, R2 and R3 each is lower alkyl and X is acetoxy.5. A compound as in claim 4 wherein each alkyl group is methyl.
 6. Acompound as in claim 5 wherein each alkyl group is ethyl.
 7. A compoundas in claim 1 wherein R is hydrogen, lower alkyl, alkali metal,trimethylsilyl or
 8. A compound of the formula